Gene therapy: Hello mothers, hello father

The Economist
02 Nov 2012A technique intended to eliminate mitochondrial diseases would result in people with three genetic parents

IS IT possible for a child to have three parents? That is the question raised by a paper just published in Nature by Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University. And the answer seems to be "yes", for this study paves the way for the birth of children who, genetically, have one father, but two mothers.

The reason this is possible is that a mother’s genetic contribution to her offspring comes in two separable pieces. By far the largest is packed into the 23 chromosomes in the nucleus of an unfertilised egg. In that, she is just like the child’s father, who provides another 23 through his sperm. But the mother also contributes what is known as mitochondrial DNA.

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Mitochondria are a cell’s power–packs. They convert the energy in sugar into a form usable by the cell’s molecular machinery. And because mitochondria descend from a bacterium that, about 2 billion years ago, became symbiotic with the cell from which animals and plants are descended, they have their own, small chromosomes. In people, these chromosomes carry only 37 genes, compared with the 20,000 or so of the nucleus. But all of the mitochondria in a human body are descended from those in the egg from which it grew. The sperm contributes none. And it is that fact which has allowed doctors to conceive of the idea of people with two mothers: one providing the nuclear DNA and one the mitochondrial sort.

The reason for doing this is that mutations in mitochondrial DNA, like those in the nuclear genes, can cause disease. These diseases especially affect organs such as the brain and the muscles, which have high energy requirements. Each particular mitochondrial disease is rare. But there are lots of them. All told, there is about one chance in 5,000 that a child will develop such an inherited disease. That rate is similar, for example, to the rate of fragile–X syndrome, which is the second–most–common type of congenital learning difficulty after Down’s syndrome. Mitochondrial disease is thus not a huge problem, but it is not negligible, either.

New batteries, please
To find out whether mitochondrial transplantation could work in people (it has already been demonstrated in other species of mammal) Dr Mitalipov collected eggs from the ovaries of women with mutated mitochondria and others from donors with healthy mitochondria. He then removed the nuclei of both. Those from the healthy cells, he discarded. Those from the diseased cells, he transplanted into the healthy cells. He then fertilised the result with sperm and allowed the fertilised eggs to start dividing and thus begin taking the first steps on the journey that might ultimately lead to them becoming full–fledged human beings.

Nearly all of the experimental eggs survived the replacement of their nuclei, and three–quarters were successfully fertilised. However, just over half of the resulting zygotes–as the balls of cells that form from a fertilised egg’s early division are known–displayed abnormalities. That compared with an abnormality rate of just an eighth in control zygotes grown from untransplanted, healthy eggs.

This discrepancy surprised–and worried–Dr Mitalipov. The abnormality rate he observed was much higher than those seen when the procedure is carried out on other species. That, though, could be because this is the first time it has been attempted with human eggs. Each species has its quirks, and if mitochondrial transplants were to become routine, the quirks of humans would, no doubt, quickly become apparent. With tweaks, they could be fixed, Dr Mitalipov predicts.

However, turning this experiment into a medical procedure would be a long road, and not just scientifically. Dr Mitalipov has little doubt that his zygotes could be brought to term if they were transplanted into a woman’s womb. That experiment, though, is illegal–and, in the view of some, rightly so. But the fact that it now looks possible will surely stimulate debate about whether the law should be changed.

Two kinds of question arise. One kind is pragmatic: would the process usually work and, if it did, would it always lead to a healthy baby who would have a normal chance of growing into a healthy adult? The second kind of question is moral, for what is being proposed is, in essence, genetic engineering. Not, perhaps, as classically conceived because no DNA is artificially modified. But it is engineering nevertheless. And that might worry some people.

On the first kind of question, the auspices are good. When Dr Mitalipov tested his zygotes, he could find no trace of mutated mitochondrial DNA in them, so the purpose of the procedure seems to have been achieved. And an experiment on monkeys that he began three years ago has produced four healthy offspring that are not apparently different from any other young monkey of their age. These are preliminary results, but they are encouraging.

It is on the moral questions that things may stumble. There is no consensus. Some people oppose such genetic tinkering in principle. Some worry about the consequences of a third adult being involved in the traditionally two–person process of parenthood–though the mitochondrial contribution is restricted to genes for energy–processing proteins and is unlikely to have wider ramifications on, say, family resemblance. Some worry that three–parented individuals may themselves be worried by knowledge of their origin. But until recently such questions have been hypothetical. Now they are real. In September, for example, Britain’s Human Fertilisation and Embryology Authority, which deals with such matters, launched a public consultation to discuss the ethics of creating three–parent offspring of the sort Dr Mitalipov proposes. This consultation runs till December 7th and the results will be given to the government in the spring.

In the end, whether three–parent children are permitted will probably depend on the public "uggh!" factor. There was once opposition to in vitro fertilisation, with pejorative terms like "test–tube baby" being bandied about. Now, IVF is routine, and it is routine because it is successful. In the case of mitochondrial transplants what will probably happen is that one country breaks ranks, permits the procedure, and the world will then see the consequences. If they are good, you will never find anyone who will admit to having opposed the transplants in the first place. If they are bad, the phrase "I told you so" will ring from the rafters.

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